Induction of effective and antigen-specific antitumour immunity by a liposomal ErbB2/HER2 peptide-based vaccination construct

Abstract

Efficient delivery of tumour-associated antigens to appropriate cellular compartments of antigen-presenting cells is of prime importance for the induction of potent, cell-mediated antitumour immune responses. We have designed novel multivalent liposomal constructs that co-deliver the p63 -71 cytotoxic T Lymphocyte epitope derived from human ErbB2 (HER2), and HA307 -319, a T-helper (Th) epitope derived from influenza haemagglutinin. Both peptides were conjugated to the surface of liposomes via a Pam 3 CSS anchor, a synthetic lipopeptide with potent adjuvant activity. In a murine model system, vaccination with these constructs completely protected BALB/c mice from subsequent s.c. challenge with ErbB2-expressing, but not ErbB2-negative, murine renal carcinoma (Renca) cells, indicating the induction of potent, antigen-specific immune responses. I.v. re-challenge of tumour-free animals 2 months after the first tumour cell inoculation did not result in the formation of lung tumour nodules, suggesting that longlasting, systemic immunity had been induced. While still protecting the majority of vaccinated mice, a liposomal construct lacking the Th epitope was less effective than the diepitope construct, also correlating with a lower number of CD8 þ IFN-g þ T-cells identified upon ex vivo peptide restimulation of splenocytes from vaccinated animals. Importantly, in a therapeutic setting treatment with the liposomal vaccines resulted in cures in the majority of tumour-bearing mice and delayed tumour growth in the remaining ones. Our results demonstrate that liposomal constructs which combine Tc and Th peptide antigens and lipopeptide adjuvants can induce efficient, antigen-specific antitumour immunity, and represent promising synthetic delivery systems for the design of specific antitumour vaccines.

DNA Vaccines Targeting Tumor Antigens to B7 Molecules on Antigen-Presenting Cells Induce Protective Antitumor Immunity and Delay Onset of HER-2/Neu-Driven Mammary Carcinoma

“…This could be explained by the absence of strong rejection antigens within the NY-ESO-1 sequence. Analysis of NY-ESO-1 using SYFPEITHI (46) and MAPPP (47) databases did not reveal peptide epitopes predicted to bind to MHC I of BALB/c mice with high affinity, whereas CTLA-4-ErbB2 222 and untargeted ErbB2 222 both contain the strong H-2K d -restricted TYLPTNASL epitope (20,32). In addition, NY-ESO-1 is an intracellular protein (29), which will limit the protective activity of potential vaccine-induced anti-NY-ESO-1 antibodies.…”

“…T-cell responses on vaccination with the CTLA-4-ErbB2 222 DNA vaccine were evaluated in ex vivo restimulation experiments followed by intracellular cytokine staining as described previously (20,32). Female BALB/c mice were vaccinated twice by intramuscular injection of plasmid DNA on days -21 and -7.…”

Antitumor activity of liposomal ErbB2/HER2 epitope peptide-based vaccine constructs incorporating TLR agonists and mannose receptor targeting

“…The aim of this study was to develop a minimalist molecularly defined anti-tumor constructs based on the use of CTL epitope peptide in combination with a Th epitope to increase their efficiency [13]. Because of their weak immunogenicity when administered alone, delivery systems were needed to allow the physical association of such peptides with different TLR ligands used as adjuvants.…”

“…1). Thus, liposomal constructs in which the peptide is linked to an anchor without adjuvant properties and associated with a free adjuvant displayed the same antitumoral efficiency than liposomal constructs in which the peptide was linked to an anchor with adjuvant properties [13].…”

“…MALP-2, Pam 2 Cys derivatives) and triacylated (Pam 3 Cys derivatives) lipopeptides, deriving from the N-terminal moiety of respective mycoplasmal and Escherichia coli lipoproteins, are powerful adjuvants which were used successfully to trigger cell activation and immune responses [9,10]. In a previous paper, we demonstrated that multivalent liposomes (Scheme 1A) containing CTL and Th epitope peptides, covalently anchored at liposome surface via Pam 3 CSS derivatives, a potent agonist of TLR2/TLR1 heterodimers [11,12] displayed potent anti-tumoral activities in both prophylactic and therapeutic vaccination settings [13]. Although highly promising, these constructs had some limitations.…”